Targeting Src in mucinous ovarian carcinoma

Koji Matsuo, Masato Nishimura, Justin N. Bottsford-Miller, Jie Huang, Kakajan Komurov, Guillermo N. Armaiz-Pena, Mian M.K. Shahzad, Rebecca L. Stone, Ju Won Roh, Angela M. Sanguino, Chunhua Lu, Dwight D. Im, Neil B. Rosenshien, Atsuko Sakakibara, Tadayoshi Nagano, Masato Yamasaki, Takayuki Enomoto, Tadashi Kimura, Prahlad T. Ram, Kathleen M. SchmelerGary E. Gallick, Kwong K. Wong, Michael Frumovitz, Anil K. Sood

Research output: Contribution to journalArticle

Abstract

Purpose: Mucinous ovarian carcinomas have a distinct clinical pattern compared with other subtypes of ovarian carcinoma. Here, we evaluated (i) stage-specific clinical significance of mucinous ovarian carcinomas in a large cohort and (ii) the functional role of Src kinase in preclinical models of mucinous ovarian carcinoma. Experimental Design: A total of 1,302 ovarian cancer patients including 122 (9.4%) cases of mucinous carcinoma were evaluated for survival analyses. Biological effects of Src kinase inhibition were tested using dasatinib-based therapy in a novel orthotopic mucinous ovarian cancer model (RMUG-S-ip2). Results: Patients with advanced-stage mucinous ovarian cancer had significantly worse survival than those with serous histology: median overall survival, 1.67 versus 3.41 years, P = 0.002; median survival time after recurrence of 0.53 versus 1.66 years, P < 0.0001. Among multiple ovarian cancer cell lines, RMUG-S-ip2 mucinous ovarian cancer cells showed the highest Src kinase activity. Moreover, oxaliplatin treatment induced phosphorylation of Src kinase. This induced activity by oxaliplatin therapy was inhibited by concurrent administration of dasatinib. Targeting Src with dasatinib in vivo showed significant antitumor effects in the RMUG-S-ip2 model but not in the serous ovarian carcinoma (SKOV3-TR) model. Combination therapy of oxaliplatin with dasatinib further showed significant effects on reducing cell viability, increasing apoptosis, and in vivo antitumor effects in the RMUG-S-ip2 model. Conclusions: Our results suggest that poor survival of women with mucinous ovarian carcinoma is associated with resistance to cytotoxic therapy. Targeting Src kinase with a combination of dasatinib andoxaliplatinmaybeanattractiveapproachforthis disease.

Original languageEnglish (US)
Pages (from-to)5367-5378
Number of pages12
JournalClinical Cancer Research
Volume17
Issue number16
DOIs
StatePublished - Aug 15 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Matsuo, K., Nishimura, M., Bottsford-Miller, J. N., Huang, J., Komurov, K., Armaiz-Pena, G. N., Shahzad, M. M. K., Stone, R. L., Roh, J. W., Sanguino, A. M., Lu, C., Im, D. D., Rosenshien, N. B., Sakakibara, A., Nagano, T., Yamasaki, M., Enomoto, T., Kimura, T., Ram, P. T., ... Sood, A. K. (2011). Targeting Src in mucinous ovarian carcinoma. Clinical Cancer Research, 17(16), 5367-5378. https://doi.org/10.1158/1078-0432.CCR-10-3176